JPS6031823B2 - Method for producing carbazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a compound of formula a, wherein R2 is hydrogen or halogen, and R3 is halogen, wherein R is lower alkyl Q-Methyl-3-oxocyclohexanemalonic acid di-lower alkyl ester of is reacted with phenylhydrazine of, where R2 and R3 are as described above, to form R,, R2 and R3 is as defined above, b treating a compound of formula W with an oxidizing agent to produce a compound of formula W, in which R,, R2 and R3 are as defined above; c It consists of hydrolyzing the compound of V.

The term "lower alkyl" means a straight or branched hydrocarbon group containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl or heptyl.

The term "halogen" means bromine, chlorine, fluorine or iodine, with bromine and chlorine being preferred. Compounds of Formula 1 are useful as anti-inflammatory, analgesic and anti-rheumatic agents.

Step a of the above process is carried out in the presence of an inert organic solvent, for example an alkanol such as methanol, ethanol or propanol, conveniently at room temperature or above.
For example, it is carried out at a temperature in the range of 25 to about 10 psi.

Compounds of formula W may be recovered using conventional methods, if desired. However, it is also possible to use the reaction product in situ in the next step of the process according to the invention. Examples of compounds of formula N are: Dimethyl-(6-chloro-1,2,3,4-tetrahydro-2-carbazolyl)-methylmalonate: Diethyl-(6-chloro-1,2,3,4-tetrahydro-2) −
Carbazolyl)-methyl malonate: dipropyl(6
-chloro-1,2,3,4-tetrahydro-2-carbazolyl)-methylmalonate: dibutyl(6-chloro-1,2,3,4-tetrahydro-2-carbazolyl)
-Methyl malonate: diethyl-(5-chloro-1,2
,3,4-tetrahydro-2-carbazolyl)-methylmalonate: diethyl(7-chloro-1,2,3,4
-tetrahydro-2-carbazolyl)-methylmalonate: and diethyl-(8-chloro-1,2,3,4-
Tetrahydro-2-carbazolyl-methylmalonate.

Examples of compounds of formula 2 are the dimethyl, diethyl, dipropyl, dibutyl and dibenthyl esters of Q-methyl-3-oxocyclohexane malonic acid.

An example of a substituted phenylhydrazine of formula m is p-chlorophenylhydrazine.

Step b of the process is carried out in a hydrocarbon solvent such as benzene, toluene or xylene.

Examples of oxidizing agents are paraquinones such as paraquinone, chloranil (tetramethyl-p-quinone), dichloroparaquinone and dicyanoparaquinone. The reaction can be carried out at room temperature to the reflux temperature of the reaction mixture, preferably at reflux temperature. Compounds of formula V can be recovered using conventional methods, such as recrystallization.

An example of a compound of formula V is 2-carbazolyl malonate, which corresponds to the 1,2,3,4-tetrahydro-2-carbazolyl malonate shown above. Hydrolysis step c can be carried out using, for example, glacial acetic acid in the presence of a hydrohalic acid such as hydrochloric acid.

The resulting product of formula 1 is recovered using conventional methods.
Example 1 In a solution of 2.5 g of sodium in ethanol 325,
Add 20 mg of methyl methyl malonate in 5 minutes.

After one hour of lighting, a solution of 10 parts of 2-cyclohexen-1-one in 130 parts of ethanol is added over a period of one hour.

The fermentation is continued overnight at room temperature, after which 20% of acetic acid is added and the mixture is evaporated under reduced pressure. Dissolve the residue in 1.31 parts of ether and wash three times with 230 parts of water. The ether solution is filtered and dried. The ether is removed under reduced pressure and the remaining oil is distilled. Q-methyl-3-oxocyclohexane malonic acid diethyl ester is 129
~180o/0.2 pig distillation: yield 211. Acid, 75.4% of theory. Example 2 Q-Methyl-3-oxocyclohexane malonic acid diethyl ester 10 females and p-chloro-phenylhydrazine hydrochloride 66. The suspension in ethanol 300' is heated for 1.5 hours at room temperature under a nitrogen atmosphere and then refluxed for 1.5 hours.

The reaction mixture is cooled in an ice bath and filtered. Wash the residue with mother liquor, suction dry the presscake, wash 3 times with 50 ml of ethanol, then wash with 50 ml of 1:1 hexane-ethanol, and dry at 40-500 ml in vacuo. let The resulting solid was dissolved with 500 ml of cold water under a nitrogen atmosphere.
Candle for 5 minutes, filter in the oven, wash three times with cold water at 100 °C, dry under vacuum at 400 °C, and diethyl (6
-Chloro-1,2,3,4-tetrahydro-2-carbazolyl)-methylmalonate78. You will get the foundation. mp
129-130o, 56.5% of theory. Example 3 Diethyl(6-chloro-1,2,3,4-tetrahydro-2-carbazolyl)-methylmalonate 161. A mixture of crab, 251.0 g of chloranil, and 1.65 g of xylene is refluxed under a nitrogen atmosphere for 6 hours and allowed to cool overnight.

The toplight is decanted and milled, the residue is triturated with three 650° portions of hot benzene, the toplight is decanted and filtered. Two portions of ether are added to the combined furnace liquors and the mixture is extracted with four 650' portions of state-of-the-art sodium hydroxide. The organic layer is washed with water until the washings are neutral, dried and evaporated under reduced pressure to dry the residue. 156. *Dissolve the solid in 300 g of boiling carbon tetrachloride, treat with 3.0 g of activated carbon, filter in an oven, dilute with 600 g of hexane, heat until boiling, and immediately dissolve the jethyl (6
Crystals of -chloro-2-carbazolyl)-methylmalonate are added as seeds, and the mixture is allowed to cool overnight while being entrained under a nitrogen atmosphere, and then cooled in a water bath. Leaving the crystalline material in the furnace,
Wash with 100 2:1 hexane-carbon tetrachloride three times each. This group, when dried under reduced pressure, yields 119. Warmth is generated. mpl34-1350, 75.2% of theory. Example 4 247 g of diethyl-(6-chloro-2-carbazolyl)methyl malonate, 1.9 g of glacial acetic acid, and 1.9 g of crucian carp hydrochloric acid.
9. The mixture was stirred under a nitrogen atmosphere and refluxed overnight;
The resulting solution is allowed to cool to room temperature.

The resulting solid is filtered, washed three times with 200 g of 1:1 acetic acid-water and four times with 300 g of water, and dried. Crude 6-chloroQ-methylcarbazole-2-acetic acid (
(ca. , acidified by adding 100% of concentrated hydrochloric acid. Pilgrimage 1
After 5 minutes, the precipitated solid is filtered, washed with 100 g of water three times and dried to give 167.7 g of product. Final purification is performed using activated carbon8. This is carried out by crystallizing boiling 1,2-dichloroethane containing 1,2-dichloroethane from 4.7 hours. The solution is allowed to stand overnight. The crystals are filtered, washed with two 200 parts of cold dichloroethane, and dried. 6-chloro-Q-methylcarbazole-2-
The yield of acetic acid is 103. Total.

Claims (1)

[Claims] 1 a Formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ In the formula, R_1 is lower alkyl, α-methyl-3-oxocyclohexanemalonic acid di-
The formula for lower alkyl esters is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R_2 is hydrogen or halogen, and R_
3 is a halogen, is reacted with phenylhydrazine of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R_1, R_2 and R_3 are as above, to produce a compound of the formula IV, b Treating the compound with an oxidizing agent to produce a compound of the formula ▲ Mathematical formula, chemical formula, table, etc. ▼ where R_1, R_2 and R_3 are as described above, c Hydrolyzing the compound of formula V An expression characterized by ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ A method for producing a compound in which R_2 and R_3 are as described above. 2. Process according to claim 1, in which p-chloro-phenylhydrazine is used as starting material of formula III.